An 86-year-old Caucasian male developed hyponatremia while on trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 mg, one tablet by mouth twice daily. Upon discontinuation of therapy, his serum sodium and symptoms improved. He was inadvertently rechallenged several months later with TMP-SMX and had similar symptoms and laboratory abnormalities. TMP-SMX-induced hyponatremia is a rare occurrence. Previous publications have most often reported this phenomenon in combination with hyperkalemia. However, this patient represents a case of TMP-SMX-induced hyponatremia independent of hyperkalemia and provides a rare opportunity to observe a challenge and rechallenge with the offending medication. Although the mechanism behind this adverse drug reaction remains unclear, a score of 7 on the Naranjo probability scale indicates a probable likelihood that TMP-SMX was the cause of the hyponatremia in this patient. This case demonstrates that TMP-SMX can result in the development of hyponatremia independent of hyperkalemia. Health care providers should be aware of the potential for hyponatremia associated with TMP-SMX and consider monitoring electrolytes and renal function during therapy.